An important role for a small, naturally occurring protein called interleukin-10 (IL-10) has been discovered by scientists. They say it helps in removing bacteria from the blood of infected mice and reversing damage to the brain.
This bacterium, Escherichia coli K1, is the most common cause of meningitis in premature infants and the second most common cause of the disease in newborns.
"The ineffectiveness of antibiotics in treating newborns with meningitis and the emergence of antibiotic-resistant strains of bacteria require new strategies," explains Nemani V. Prasadarao, Ph. D, associate professor of infectious disease at Childrens Hospital Los Angeles (CHLA).
Rahul Mittal, lead author on the paper and a post-doctoral fellow in Prasadarao's lab, said: "We found that during an episode of bacteremia, when a large number of bacteria are circulating in normally sterile blood, IL-10 acts to clear antibiotic-sensitive as well as antibiotic-resistant E. coli from the circulation of infected mice."
They also determined that E. coli infection produced damage to the mouse brain comparable to that seen in humans. Three-dimensional imaging studies of infected animal and human infant brains showed similar gross morphological changes.
"When we gave IL-10 to mice 48 hours after infection, those changes to the brain were reversed," said Mittal.
Tumor necrosis factor (TNF) is a cytokine active in producing inflammation. When the researchers replicated these experiments using antibiotic or anti-TNF, brain damage resulting from E. coli infection was not prevented.
The team also discovered a mechanism of action for IL-10 protection. In culture, using mouse and human white blood cells called neutrophils, they found that exposing these cells to IL-10 produced an increase in the number of a certain type of receptor on the surface of the neutrophils. An increase in the CR 3 receptor led to enhanced killing of bacteria.
Another white blood cell, called a macrophage, works to clear bacteria from the blood by engulfing or "eating" the pathogen. Similar to what was seen in neutrophils, macrophages treated with IL-10 showed an increase in CR 3 receptors that enhanced their ability to destroy invading bacteria.
To confirm that the CR 3 receptor is critical to the protective effect of IL-10 against E. coli, CR 3 expression was suppressed in a group of mice. Before exposing the animals to bacteria, white blood cells were examined and the CR 3 receptor was determined to be absent. These animals were exposed to E. coli and then treated with IL-10.
The mice were found subsequently to have bacteria in the CSF and morphological changes indicating brain damage. The protective effect of IL-10 during bacteremia was absent in animals without CR 3 receptors. The researchers further concluded that the crucial increase in CR 3 receptor was a result of IL-10 suppressing an important inflammatory agent, prostaglandin E-2.
"Since diagnosing meningitis is difficult until bacteria reach the central nervous system, finding an agent that can clear the bacteria while also preventing or restoring the damaged brain is very exciting," said Mittal.
The study, conducted in collaboration with the Keck School of Medicine of the University of Southern California and the Universite Auvergne, France, has been published in the Journal of Experimental Medicine.